The present invention relates to tricyclic compounds and intermediates thereof with a side chain having an anilino moiety having an acyl coenzyme A: cholesterol acyltransferase (hereafter referred to as ACAT) inhibiting activity. The compounds are useful for the treatment of hyperlipemia and arteriosclerosis.
Myocardial infarction or cerebral infarction caused by arteriosclerosis has been ranked as high mortality in advanced countries, along with cancer. It has thus been desired to develop a medicine for the treatment of arterio-sclerosis. Based on the results of many epidemiological investigations, it has already been pointed out that hyper-cholesterolemia is one of risk factors of arteriosclerosis. It has been reported that development of arteriosclerosis is prevented by reducing cholesterol level in blood serum, inter alia, cholesterol level with low density lipoprotein (LDL).
Cholesterol is supplied in vivo by biosynthesis and absorption. Compounds which inhibit biosynthesis and absorption might reduce cholesterol level in blood serum. As compounds having an activity of inhibiting absorption, nicotinic acid derivatives and sterols originated from plants are known. However, their activity is not sufficient.
Cholesterol is absorbed on epithelial cells of the intestine in its free form, then esterified by ACAT, included in chylomicron, and transported to liver by blood stream in chylomicron form. ACAT plays an important role in accumulation of cholesterol in liver. ACAT is also involved in transformation of macrophage to foam cell. ACAT is thought to cause progression of arteriosclerosis [J. Lipid Res., 26, 647 (1985); Nippon Rinsho (Clinic in Japan), 47, 554 (1989)]. Compounds which inhibit ACAT might inhibit the absorption of cholesterol and accumulation of cholesterol in liver. Therefore, these effects accelerate excretion of cholesterol and consequently reduce cholesterol level in blood serum. Furthermore, such compounds inhibit the formation of foam cells and are thus expected to be effective for the treatment of hyperlipemia and arteriosclerosis.
Compounds represented by formula (A) which possess an ACAT inhibitory activity are disclosed in U.S. Pat. No. 4,489,090. ##STR2##
It is also described in Heterocycles, 12, 637 (1979) that compounds represented by formula (B): ##STR3## wherein R represents ethoxy or chlorine, have an anti-leukemia activity and antispasmodic activity.
The compounds represented by the formula (C): ##STR4## wherein T represents oxygen was described in Czech. CS., 202, 336. [Chem. Abst., 98, 89198q (1983)] and wherein T represents CH.sub.2 was described in J. Am. Chem. Soc., 106. 4175 (1984).